Fig. 2.

Type II NKT cells suppress tumor immunity.

When type II NKT cells (mostly CD4⁺) are activated by tumor-derived glycolipids presented by CD1d, they produce IL-13. Together with TNF-α in the microenvironment signaling through TNF-receptor (TNFR) and NF-κB, IL-13 signals through a type II IL-4 receptor (IL-4R), a heterodimer of an IL-4Rα and an IL-13Rα1, and STAT6 to induce expression of the IL-13Rα2 on a CD11b⁺Gr-1⁺ myeloid cell. The IL-13Rα2 binding to IL-13 transduces a signal through AP-1, which induces expression of TGF-β. TGF-β suppresses activation of tumor specific CD8⁺ T cells, which mediate regression of tumors. In some tumor settings, IL-13 may induce M2 macrophages that also suppress CD8⁺ T cells. Blockade of either IL-13 by an IL-13 inhibitor such as soluble IL-13Rα2, or TGF-β with anti-TGF-β antibodies, or TNF-α with a TNF-α antagonist can remove the suppression. Modified from (Terabe, et al., 2003a) with permission.